Transmembrane_receptor by zzzmarcus


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Membrane receptor

Membrane receptor
membrane receptors with various amounts on its surface. A certain receptor may also have different concentrations on different membrane surfaces, depending on the membrane and cell function. The receptors usually form “clusters” on the membrane surface[2][3], therefore the distribution of receptors on membrane surface is mostly heterogeneous. Epinephrine binds its receptor, that associates with an heterotrimeric G protein. The G protein associates with adenylate cyclase that converts ATP to cAMP, spreading the signal (more details...) Membrane or Transmembrane receptors are specialized integral membrane proteins that take part in communication between the the cell and the outside world. Extracellular signal molecules (usually hormones or cell recognition molecules) attach to the receptor, triggering changes in the function of the cell. This process is called signal transduction: The binding initiates a chemical change on the intracellular side of the membrane. In this way the receptors play a unique and important role in cellular communications and signal transduction. Many transmembrane receptors are composed of two or more protein subunits which operate collectively and may dissociate when ligands bind, fall off, or at another stage of their "activation" cycles. They are often classified based on their molecular structure, or because the structure is unknown in any detail for all but a few receptors, based on their hypothesized (and sometimes experimentally verified) membrane topology. The polypeptide chains of the simplest are predicted to cross the lipid bilayer only once, while others cross as many as seven times (the socalled G-protein coupled receptors). There are various kinds such as glycoprotein and lipoprotein.[1] Hundreds of different receptors are known and many more are yet to be discovered. Almost all known membrane receptors are transmembrane proteins. A certain cell membrane can have several

Like any integral membrane protein, a transmembrane receptor may be subdivided into three parts or domains.

E=extracellular space; I=intracellular space; P=plasma membrane

Extracellular domain
The extracellular domain is the part of the receptor that sticks out of the membrane on the outside of the cell or organelle. If the polypeptide chain of the receptor crosses the bilayer several times, the external domain can comprise several "loops" sticking out of the membrane. By definition, a receptor’s main function is to recognize and respond to a specific ligand, for example, a neurotransmitter or hormone (although certain receptors respond also to changes in transmembrane potential), and in many receptors these ligands bind to the extracellular domain.

Transmembrane domain
In the majority of receptors for which structural evidence exists, transmembrane alpha helices make up most of the transmembrane domain. In certain receptors, such as the


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nicotinic acetylcholine receptor, the transmembrane domain forms a protein-lined pore through the membrane, or ion channel. Upon activation of an extracellular domain by binding of the appropriate ligand, the pore becomes accessible to ions, which then pass through. In other receptors, the transmembrane domains are presumed to undergo a conformational change upon binding, which exerts an effect intracellularly. In some receptors, such as members of the 7TM superfamily, the transmembrane domain may contain the ligand binding pocket (evidence for this and for much of what else is known about this class of receptors is based in part on studies of bacteriorhodopsin, the detailed structure of which has been determined by crystallography).

Membrane receptor
• are either enzymes themselves, or are directly associated with the enzymes that they activate. These are usually singlepass transmembrane receptors, with the enzymatic portion of the receptor being intracellular. The majority of enzyme-lined receptors are protein kinases, or associate with protein kinases. • are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. These receptors activate a G protein ligand binding. G-protein is a trimeric protein. The 3 subunits are called α?β and γ. The α subunit can bind with guanosine diphosphate, GDP. This causes phosphorylation of the GDP to guanosine triphosphate, GTP, and activates the α subunit, which then dissociates from the β and γ subunits. The activated α subunit can further affect intracellular signaling proteins or target functional proteins directly.

Intracellular domain
The intracellular (or cytoplasmic) domain of the receptor interacts with the interior of the cell or organelle, relaying the signal. There are two fundamentally different ways for this interaction: • The intracellular domain communicates via specific protein-protein-interactions with effector proteins, which in turn send the signal along a signal chain to its destination. • With enzyme-linked receptors, the intracellular domain has enzymatic activity. Often, this is a tyrosine kinase activity. The enzymatic activity can also be located on an enzyme associated with the intracellular domain.

Signal Transduction

The External Reactions and the Internal Reactions for signal transduction Signal transduction process through membrane receptors involve the External Reactions in which the ligand binds to a membrane receptor and the Internal Reactions in which intracellular response is triggered[4][5]. Signal transduction through membrane receptors usually requires 4 characters: 1. Extracellular signal molecule: an extracellular signal molecule is produced by one cell and is capable of traveling to neighboring cells, or to cells that may be far away. 2. Receptor protein: the cells in an organism must have cell surface receptor proteins that bind to the signal molecule and communicate its presence inward into the cell. 3. Intracellular signaling proteins: these distribute the signal to the appropriate parts of the cell. The binding of the signal molecule to the receptor protein

Based on structural and functional similarities, membrane receptors are mainly divided into 3 classes: The ion channel-linked receptor; The enzyme-linked receptor and G protein-coupled receptor. • are ion-channels (including cationchannels and anion-channels) themselves and constitute a large family of multipass transmembrane proteins. They are involved in rapid signaling events most generally found in electrically excitable cells such as neurons and are also called ligand-gated ion channels. Opening and closing of Ion channels are controlled by neurotransmitters.


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will activate intracellular signaling proteins that initiate a signaling cascade (a series of intracellular signaling molecules that act sequentially). 4. Target proteins: the conformations or other properties of the target proteins are altered when a signaling pathway is active and changes the behavior of the cell[5].

Membrane receptor

Enzyme-Linked Receptors

Ion Channel-Linked Receptor
example sketch of an enzyme-linked receptor structure (structure of IGF-1R) As of 2009, there are 6 known types of enzyme-linked receptors: Receptor tyrosine kinases; Tyrosine kinases associated receptors; Receptor-like tyrosine phosphatases; Receptor serine/threonine kinases; Receptor Guanylyl cyclases and Histidine kinase associated receptors. Receptor tyrosine kinases is the one kind with the largest population and most widely application. The majority of these molecules are receptors for growth factors and hormones like epidermal growth factor (EGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor(HGF), insulin, nerve growth factor (NGF) etc. Most of these receptors will dimerize after binding with their ligands in order to activate further signal transductions. For example, after the epidermal growth factor (EGF) receptor binds with its ligand EGF, two receptors dimerize and then undergo phosphorylation of the tyrosine residues in the enzyme portion of each receptor molecule, which will activate the tyrosine protein kinase and analyze further intracellular reactions.

Three conformation states of acetylcholine receptor In the signal transduction event in a neuron, the neurotransmitter binds with the receptor and alters the conformation of the protein, which opens the ion-channel, allowing extracellular ions go into the cell. The ion permeability of the plasma membrane is altered, and this will instantaneously convert the extracellular chemical signal into intracellular electric signal, which will alter the excitability of the cell[6]. Acetylcholine receptor is a kind of cationchannel linked receptor. The protein consists of 4 subunits: α, β, γ, and δ subunits. There are two α subunits, containing one acetylcholine binding site each. This receptor can exist in three different conformations. The unoccupied-closed state is the protein at its original conformation. After two molecules of acetylcholine bind simultaneously to the binding sites on α subunits, the conformation of the receptor is altered and the gate is opened, allowing for the penetration of many ions and small molecules. However, this occupied-open state can only last for a very short period of time and then the gate is closed again, forming the occupied-closed state. The two molecules of acetylcholine will quickly dissociate from the receptor and the receptor will returns to its unoccupied-closed state and is ready for next transduction cycle again[7][8].

G Protein-Linked Receptors
There are two principal signal transduction pathways involving the G-protein linked receptors: cAMP signal pathway and Phosphatidylinositol signal pathway[9]. cAMP signal pathway The cAMP signal transduction contains 5 main characters: stimulative hormone receptor (Rs) or inhibitory hormone receptor (Ri)?Stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi)?Adenylyl cyclase; Protein Kinase A (PKA); and cAMP phosphodiesterase. Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules, while inhibitory hormone (Ri) is a


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Membrane receptor

Activation effects of cAMP on Protein Kinase A

The effect of Rs and Gs in cAMP signal pathway

G protein-linked receptor mechanism

The effect of Ri and Gs in cAMP signal pathway receptor that can bind with inhibitory signal molecules. Stimulative regulative G-protein is a Gprotein linked to stimulative hormone receptor (Rs) and its α subunit upon activation could stimulate the activity of an enzyme or other intracellular metabolism. On the contrary, inhibitory regulative G-protein is a linked to an inhibitory hormone receptor and its α subunit upon activation could inhibit the

Dissociation/association of the G protein


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activity of an enzyme or other intracellular metabolism. The Adenylyl cyclase is a 12 transmembrane glucoprotein that catalyzes ATP to form cAMP with the help of cofactor Mg2+or Mn2+. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator to Protein kinase A. Protein kinase A is an important enzyme in cell metabolism due to its ability to regulate cell metabolism by phosphorylating specific committed enzyme in matabolic pathway and it can also regulate specific gene expression, cellular secretion and membrane permeability. The protein enzyme contains two catalytic subunits and two regulative subunits. When there is no cAMP?the complex is inactive. After cAMP binds with the regulative subunits, it alters the conformation of these subunits, causing the dissociation of the regulative subunits, which activate protein kinase A and allow for further biological effects. cAMP phosphodiesterase is an enzyme that can degrade cAMP to 5’-AMP, which will terminate the signal. Phosphatidylinositol signal pathway In phosphatidylinositol signal pathway the extracellular signal molecule binds with the Gprotein receptor on cell surface and active phospholipase C which is located on the plasma membrane. The lipase hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messegers: Inositol 1,4,5-triphosphate (IP3) and Diacylglycerol (DAG). IP3 binds with the receptor in the membrane of the smooth endoplasmic reticulum and mitochondria, help open the Ca2+ channel and DAG will help activate Protein Kinase C (PKC), which will cause series of biological effects. DAG will help activate Protein Kinase C, which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses. The effects of Ca2+ is also remarkable: it cooperates with DAG in activating PKC and can activate CaM kinase pathway, in which calcium modulated protein calmodulin (CaM) binds Ca2+, undergoes a change in conformation, and activates CaM kinase II, which has unique ability to increase its binding affinity to CaM by autophosphorylation, making CaM unavailable for the activation of other enzymes. The kinase then phosphorylates target enzymes, regulating their activities. The two signal pathways are connected together by Ca2+-CaM, which is

Membrane receptor
also a regulatory subunit of adenylyl cyclase and phosphodiesterase in cAMP signal pathway.

Membrane Receptor Related Disease
If the membrane receptors are altered directly or deficient for some reason, the signal transduction can be hindered and cause diseases. Some diseases are caused by membrane receptor function disorder due to deficiency or disorder of the receptor induced by the change in the genes that encode the receptor protein. Scientists recently have found that the membrane receptor TM4SF5 has something to do with the migration ability of hepatic cells and hepatoma.[10] and that the cortical NMDA receptor properties and membrane fluidity are altered in Alzheimer’s disease.[11] Also, when the cell is infected by nonenveloped virus, the virus first binds with certain membrane receptors and then somehow the virus or some subviral component ends up on the cytoplasmic side of a cellular membrane, the plasma membrane for some viruses or the membrane of an endosomal vesicle for others. In the case of poliovirus, it is known that interactions with receptors in vitro will lead to conformational rearrangements of the virion that result in the release of one of the virion proteins, called VP4.The N terminal of VP4 is myristylated and thus hydrophobic?myristic acid=CH3(CH2)12COOH?. It is proposed that the conformational changes induced by receptor binding result in the insertion of the myristic acid on VP4 into the cell membrane and the formation of a channel through which the RNA can enter the cell.

Structure-Based Drug Design for Membrane Receptors
As the experimental methods as X-ray crystallography and NMR develop, the amount of information concerning 3D structures of biomolecular targets has increased dramatically, as well as the structural dynamic and electronic information about the ligands. This encourages the rapid development of the structure-based drug design. Current methods for structure-based drug design can be


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Membrane receptor
• : all carbons in hydrocarbon chains or in aromatic groups. • : Oxygen and nitrogen atoms bonded to hydrogen atom(s). • : Oxygen and sp2 or sp hybridized nitrogen atoms with lone electron pair(s). • : Oxygen and nitrogen atoms that are neither H-bond donor nor H-bond acceptor, sulfur, phosphorus, halogen, metal and carbon atoms bonded to heteroatom(s). The space inside the ligand binding region would be studied with virtual probe atoms of the four types above so the chemical environment of all spots in the ligand binding region can be known. Hence we are clear what kind of chemical fragments can be put into their corresponding spots in the ligand binding region of the receptor.

Flow charts of two strategies of structurebased drug design divided roughly into two categories. The first category is about “finding” ligands for a given receptor, which is usually referred as database searching. In this case, a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. This method is usually referred as ligand-based drug design. The key advantage of database searching is that it saves synthetic effort to obtain new lead compounds. Another category of structurebased drug design methods is about “building” ligands, which is usually referred as receptor-based drug design. In this case, ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner. These pieces can be either atoms or fragments. The key advantage of such a method is that novel structures, not contained in any database, can be suggested. These techniques are raising much excitement to the drug design community[12][13][14].

Ligand fragment link

Flow chart for structure based drug design When we want to plant “seeds” into different regions defined by the previous section, we need a fragments database to choose fragments from. The term “fragment” is used here to describe the building blocks used in the construction process. The rationale of this algorithm lies in the fact that organic structures can be decomposed into basic chemical fragments. Although the diversity of organic structures is infinite, the number of basic fragments is rather limited. Before the first fragment, i.e. the seed, is put into the binding pocket, and add other fragments one by one. we should think some problems. First, the possibility for the fragment combinations is huge. A small perturbation of the previous fragment conformation

Active site identification
Active site identification is the first step in this program. It analyzes the protein to find the binding pocket, derives key interaction sites within the binding pocket, and then prepares the necessary data for Ligand fragment link. The basic inputs for this step are the 3D structure of the protein and a pre-docked ligand in PDB format, as well as their atomic properties. Both ligand and protein atoms need to be classified and their atomic properties should be defined, basically, into four atomic types:


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would cause great difference in the following construction process. At the same time, in order to find the lowest binding energy on the Potential energy surface (PES) between planted fragments and receptor pocket, the scoring function calculation would be done for every step of conformation change of the fragments derived from every type of possible fragments combination. Since this requires a large amount of computation, one may think using other possible strategies to let the program works more efficiently. When a ligand is inserted into the pocket site of a receptor, conformation favor for these groups on the ligand that can bind tightly with receptor should be taken priority. Therefore it allows us to put several seeds at the same time into the regions that have significant interactions with the seeds and adjust their favorite conformation first, and then connect those seeds into a continuous ligand in a manner that make the rest part of the ligand having the lowest energy. The conformations of the pre-placed seeds ensuring the binding affinity decide the manner that ligand would be grown. This strategy reduces calculation burden for the fragment construction efficiently. On the other hand, it reduces the possibility of the combination of fragments, which reduces the number of possible ligands that can be derived from the program. These two strategies above are well used in most structure-based drug design programs. They are described as “Grow” and “Link”. The two strategies are always combined in order to make the construction result more reliable[12][13][15].

Membrane receptor
overall binding free energy can be decomposed into independent components which are known to be important for the binding process. Each component reflects a certain kind of free energy alteration during the binding process between a ligand and its target receptor. The Master Equation is the linear combination of these components. According to Gibbs free energy equation, the relation between dissociation equilibrium constant, Kd and the components of free energy alternation was built.

The sub models of empirical functions differ due to the consideration of researchers. It has long been a scientific challenge to design the sub models. Depend on the modification of them, the empirical scoring function is improved and continuously consummated[17][18][19].

See also
• • • • Signal transduction G protein Second messenger Neuromodulators

Other examples
• • • • • • • • • • Adrenergic receptor, Olfactory receptors, Receptor tyrosine kinases Epidermal growth factor receptor Insulin Receptor Fibroblast growth factor receptors, High affinity neurotrophin receptors Eph Receptors Integrins Low Affinity Nerve Growth Factor Receptor • NMDA receptor • Several Immune receptors • Toll-like receptor • T cell receptor • CD28

Scoring method
Structure-based drug design attempts to use the structure of proteins as a basis for designing new ligands by applying accepted principles of molecular recognition. The basic assumption underlying structure-based drug design is that a good ligand molecule should bind tightly to its target. Thus, one of the most important principles for designing or obtaining potential new ligands is to predict the binding affinity of a certain ligand to its target and use it as a criterion for selection. A breakthrough work was done by Böhm[16] to develop a general-purposed empirical function in order to describe the binding energy. The concept of the “Master Equation” was raised. The basic idea is that the

External links
• IUPHAR GPCR Database • MeSH Cell+Surface+Receptors


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Membrane receptor
expression in human cancer". Gene 208 (1): 25-30. doi:10.1016/ S0378-1119(97)00633-1. [11] Scheuer K., Marasb A., Gattazb W.F., Cairnsc N., Förstlb H., Müller W.E. (1996). "Cortical NMDA Receptor Properties and Membrane Fluidity Are Altered in Alzheimer’s Disease". Dementia 7 (4): 210-214. doi:10.1159/ 000106881. [12] ^ Wang R.,Gao Y.,Lai L. (2000). "LigBuilder: A Multi-Purpose Program for Structure-Based Drug Design". Journal of Molecular Modeling 6: 498–516. doi:10.1007/s0089400060498. [13] ^ Schneider G., Fechner U. (2005). "Computer-based de novo design of drug-like molecules". Nature Reviews Drug Discovery 4: 649-663. doi:10.1038/ nrd1799. [14] Jorgensen W.L. (2004). "The Many Roles of Computation in Drug Discovery". Science 303: 1813-1818. doi:10.1126/ science.1096361. [15] Verlinde C., Hol.W (1994). "Structurebased drug design: progress, results and challenges". Structure 2 (7): 577-587. doi:10.1016/S0969-2126(00)00060-5. [16] Böhm H.J. (1994). "The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known threedimensional structure". Journal of Computer-Aided Molecular Design 8: 243-256. doi:10.1007/BF00126743. [17] Gohlkea H.,Hendlicha M.,Klebe G. (2000). "Knowledge-based scoring function to predict protein-ligand interactions". Journal of Molecular Biology 295 (2): 337-356. doi:10.1006/ jmbi.1999.3371. [18] Clark R.D., Strizhev A., Leonard J.M., Blake J.F., Matthew J.B. (2002). "Consensus scoring for ligand/protein interactions". Journal of Molecular Graphics and Modelling 20 (4): 281-295. doi:10.1016/S1093-3263(01)00125-5. [19] Wang R.,Lai L., Wang S. (2002). "Further development and validation of empirical scoring functions for structure-based binding affinity prediction". Journal of Computer-Aided Molecular Design 16: 11-26. doi:10.1023/A:1016357811882.

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Membrane receptor

Categories: Transmembrane receptors, Cell signaling, Receptor tyrosine kinases This page was last modified on 17 May 2009, at 14:27 (UTC). All text is available under the terms of the GNU Free Documentation License. (See Copyrights for details.) Wikipedia® is a registered trademark of the Wikimedia Foundation, Inc., a U.S. registered 501(c)(3) taxdeductible nonprofit charity. Privacy policy About Wikipedia Disclaimers


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